A protein called LAP1 it makes melanoma, the most serious type of skin cancer, more aggressive by giving cancer cells the ability to change the shape of their nucleus, a characteristic that allows the cells to migrate and spread throughout the body.
Research led by Queen Mary University of London, King’s College London and the Francis Crick Institute (United Kingdom), published today in “Nature Cell Biology”, describes the behavior of aggressive melanoma cells capable of changing the shape of their nucleus to overcome the physical limitations that cancer cells encounter when migrating through tissues.
The study found that these aggressive melanoma cells harbored high levels of the LAP1 protein and that increased levels of this protein were associated with a poor prognosis in melanoma patients.
Melanoma is a type of skin cancer that can spread to other organs in the body. The spread of cancer or “metastasis” is the leading cause of cancer death. Although metastasis has been extensively studied, the mechanisms by which it occurs are not well understood. The study results shed new light on a mechanism of melanoma progression and could pave the way for the development of new ways to combat its spread.
The researchers, co-led by Victoria Sanz-Morenodel Queen Mary’s Barts Cancer Institute, y Jeremy Carltonof King’s College de Londres and the Francis Crick Institute, analyzed the behavior of aggressive and less aggressive melanoma cells in the laboratory. The aggressive cells came from a metastatic focus in a patient with melanoma, and the less aggressive cells came from the original or “primary” melanoma tumor of the same patient.
To “metastasize,” cancer cells have to break away from the primary tumor, move to another part of the body, and start growing there. However, the dense environment of a tumor makes this task physically difficult for cancer cells.
Cells contain a large, rigid structure called the nucleus that stores the cell’s genetic information, but also restricts a cell’s ability to move through the narrow gaps in the tumor environment. For cancer cells to slip through these gaps, they need their nucleus to be more malleable.
The images obtained after the migration experiments showed that the aggressive cells were able to move through the pores more efficiently than the less aggressive ones, forming protuberances at the edge of their nucleus called “blebs”. Genetic analyzes of the melanoma cells revealed that the aggressive cells that formed the bumps contained higher levels of the LAP1 protein, which is found within the membrane that surrounds the nucleus (called the nuclear envelope).
When the team blocked the production of the LAP1 protein in the aggressive cells and forced them back to migrate through the pores in lab experiments, they found that the cells were less able to bulge out of the nuclear envelope and squeeze through. these holes.
The study could pave the way for the development of new ways to combat its spread.
The team also observed the same pattern of LAP1 expression in melanoma samples from patients. LAP1 levels were higher in tissue samples taken from metastatic sites in melanoma patients, compared to levels found in primary tumors. Patients with elevated levels of LAP1 in cells around the edge of the primary tumor had more aggressive cancer and poorer outcomes, suggesting that the protein could be used to identify subpopulations of melanoma patients at higher risk of aggressive disease. .
Melanoma is the most aggressive and deadly type of skin cancer. We have gained new insights into how LAP1 contributes to melanoma progression, and have shown that LAP1 is a key regulator of melanoma aggressiveness in laboratory and patient models.” Sanz Moreno.
“Since LAP1 is expressed at such high levels in metastatic cells, interfering with this molecular machinery could have a major impact on the spread of cancer. Currently, there are no drugs that directly target LAP1.so going forward we would like to investigate ways to target LAP1 and nuclear envelope bleaching to see if it is possible to block this mechanism of melanoma progression.”